Normal tension glaucoma is one type of glaucoma and is a disease recently getting attention particularly due to its high prevalence rate. In general, glaucoma is a disease characterized by elevated intraocular pressure (watery fluid pressure within the eyeball) resulting in compression of the optic nerve to produce atrophy and thus impairing the visual performance to narrow the visual field. If it is left untreated, the symptoms will eventually progress to blindness at a high risk. On the other hand, normal tension glaucoma is a pathological condition that mimics the findings on glaucoma with high intraocular pressure (optic atrophy and visual field defects), notwithstanding that the intraocular pressure lies within the normal range (usually 10-21 mmHg in human). In the developed countries, glaucoma is ranked as the second leading cause of vision loss next to diabetes mellitus. The prevalence of glaucoma in the population aged over 40 years is 3.5% in Japan and the number of patients is estimated to be about two million. According to a recent epidemiological survey, reportedly 70% of glaucoma is normal tension glaucoma. Because of slow progress and paucity of subjective symptoms, it is difficult to detect normal tension glaucoma at an early stage. At present, there is no decisive treatment except to further decrease the intraocular pressure.
In recent years, degenerative loss of retinal ganglion cells, namely, neuronal apoptosis, which is induced by a mild and chronic increase of glutamate level, is proposed to be one of the causes of glaucoma and diabetic retinopathy (Harada, T., et al. Proc. Natl. Acad. Sci. USA, 95, 4663-4666, 1998; Harada, C. et al., Neurosci. Lett., 292, 134-136, 2000).
In the mammalian central nervous system, glutamate is one of the main excitatory neurotransmitters and plays an important role in regulating a higher order function of the brain. On the other hand, it is known that glutamate causes neurotoxicity by an excessive rise, resulting in various neurodegenerative diseases or delayed neuronal cell death after cerebral ischemia. One of the mechanisms for regulating the level of this glutamate is glutamate transporters. Glutamate transporters are functional molecules, the main role of which is to take up glutamate once released from nerve endings into cells and maintain a low glutamate level at the synaptic cleft.
Currently, EAAC1, EAAT4 and EAAT5 (Kanai, Y. & Heidiger, M. A., Nature, 360, 467-471, 1992; Fairman, W. A., et al., Nature, 375, 599-603, 1995; Arrizal, J. E., et al., Proc. Natl. Acad. Sci. USA, 94, 4155-4160, 1997) present in neurons as well as GLT1 and GLAST (also referred to as GluT-1) present in glial cells (Pines, D. et al., Nature, 360, 464-467, 1992; Mukainaka et al., Biochimica et Biophysica Acta, 1244, 233-237, 1995; Tanaka, K., Neurosci. Res., 16, 149-153, 1993; Tanaka, K., Neurosci. Lett., 159, 183-186, 1993; Storck, T., et al., Proc. Natl. Acad. Sci. USA, 89, 10955-10959, 1992) are known as glutamate transporters in the mammalian brain. Abnormalities in the function of these glutamate transporters are known to be associated with various neurodegenerative diseases.
Under such circumstances, it has become clear that GLAST is present in Müller cells within the retina and retinal damages after ischemic load are exacerbated in GLAST knockout mice as compared to wild-type mice, based on the experiments using GLAST knockout mice (Watase, K. et al, Eur. J. Neurosci., 10, 976-988, 1998; Japanese Patent Laid-Open Application No. 10-33087). For this reason, it is suggested that GLAST present in Müller cells of the retina would be involved in the onset of glaucoma (Harada, T., et al., Proc. Natl. Acad. Sci. USA, 95, 4663-4666, 1998). However, unless ischemic load is applied, damage to the retinal tissue is not observed in this GLAST knockout mouse so that the mouse cannot be used as a model for normal tension glaucoma.
For the development of therapeutics for glaucoma and the elucidation of its onset mechanism, genetically chronic glaucoma model mice or high tension glaucoma model rabbits induced by water loading are already available as glaucoma model animals, but no model animal for normal tension glaucoma has ever been known heretofore. Also, there is no report to point out the relation of normal tension glaucoma to GLAST, and the onset mechanism of normal tension glaucoma yet remains unknown.
Accordingly, it is expected that if a model animal for normal tension glaucoma is obtained, the animal will be extremely useful for developing therapeutics effective for the treatment of said disease, establishing a remedy therefor and identifying the cause of said disease or its onset mechanism. However, any model animal for normal tension glaucoma is unknown at present and, such a model animal has been earnestly desired in the medical or pharmaceutical field.